{"gene":"RPGRIP1L","run_date":"2026-06-10T06:43:37","timeline":{"discoveries":[{"year":2007,"finding":"RPGRIP1L protein colocalizes at the basal body and centrosomes with NPHP6 and NPHP4 protein products; CORS-associated missense mutations in RPGRIP1L diminish the interaction between RPGRIP1L and nephrocystin-4 (NPHP4).","method":"Colocalization imaging; co-immunoprecipitation; missense mutation analysis","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with mutation disruption of interaction, single lab, two orthogonal methods","pmids":["17558409"],"is_preprint":false},{"year":2007,"finding":"RPGRIP1L interacts with nephrocystin-4 (NPHP4), and NPHP4 mutations known to cause Senior-Løken syndrome disrupt this interaction; RPGRIP1L protein localizes to basal bodies.","method":"Protein-protein interaction analyses; co-immunoprecipitation; subcellular localization imaging","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with disease-mutation disruption, single lab, two orthogonal methods","pmids":["17558407"],"is_preprint":false},{"year":2009,"finding":"RPGRIP1L interacts biochemically with RPGR (retinitis pigmentosa GTPase regulator), and the common variant A229T (Thr229-encoded protein) significantly compromises this interaction, thereby modifying retinal degeneration in ciliopathies.","method":"Biochemical interaction assay (co-immunoprecipitation); genetic modifier analysis","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with allele-specific disruption, multiple genetic lines of evidence, single lab","pmids":["19430481"],"is_preprint":false},{"year":2009,"finding":"RPGRIP1L (KIAA1005/TPIP) directly interacts with the C-terminal region of both thromboxane A2 receptor isoforms TPα and TPβ, reduces cell-surface TP levels, and negatively regulates TP-mediated phosphoinositide hydrolysis, ERK1/2 phosphorylation, and IL-6 production.","method":"Yeast two-hybrid; co-immunoprecipitation in HEK293 cells; functional signaling assays","journal":"Prostaglandins & other lipid mediators","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus functional readouts, single lab, multiple orthogonal methods","pmids":["19464661"],"is_preprint":false},{"year":2010,"finding":"Reduced expression of Rpgrip1l impairs leptin receptor isoform b (Leprb) trafficking to the vicinity of the cilium in hypothalamic/neuroblastoma cells in vitro, and this trafficking to the cilium coincides with increased leptin signaling (pStat3). CUX1 isoforms P200 and P110 regulate RPGRIP1L expression via a conserved AATAAATA element in the FTO intronic region.","method":"siRNA knockdown; promoter-probe assays; immunofluorescence for leptin receptor clustering; pStat3 western blot","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (knockdown, promoter assay, receptor trafficking, signaling readout), single lab","pmids":["21037323"],"is_preprint":false},{"year":2011,"finding":"RPGRIP1L and RPGRIP1 each form a complex with the serine/threonine kinase NEK4, identified by tandem affinity purification and mass spectrometry; NEK4 localizes to basal bodies in ciliated cells and to the ciliary rootlet in ciliated organs. Downregulation of NEK4 significantly decreases cilium assembly.","method":"Tandem affinity purification combined with mass spectrometry; immunofluorescence; siRNA knockdown","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — TAP-MS identification of complex plus localization plus functional knockdown, single lab","pmids":["21685204"],"is_preprint":false},{"year":2012,"finding":"Rpgrip1l is required for planar cell polarity: it positions the basal body along the planar polarity axis in mouse cochlea and zebrafish floor plate, stabilizes Dishevelled at the cilium base, and forms a complex with inversin and nephrocystin-4 that prevents Dishevelled degradation. Rescue experiments in zebrafish showed that the planar polarity function of Rpgrip1l is mediated through Dishevelled stabilization.","method":"Mouse and zebrafish genetic loss-of-function; rescue experiments; co-immunoprecipitation complex analysis; immunofluorescence","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function in two model organisms, rescue experiments, Co-IP complex, multiple orthogonal methods, specific cellular phenotype","pmids":["22927466"],"is_preprint":false},{"year":2014,"finding":"Rpgrip1l hypomorphic (Rpgrip1l+/-) mice are hyperphagic and obese, display diminished suppression of food intake in response to leptin, reduced AcIII-positive cilia in the hypothalamus, and impaired convening of the leptin receptor to the vicinity of the cilium accompanied by diminished pStat3 in response to leptin.","method":"Mouse hypomorphic genetics; leptin challenge assays; immunofluorescence for cilia and leptin receptor; pStat3 measurement","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse genetic model plus human fibroblast validation, multiple orthogonal methods, replicated across labs","pmids":["24807221"],"is_preprint":false},{"year":2015,"finding":"Rpgrip1l (MKS-5 in C. elegans) functions as an assembly factor for the ciliary transition zone (TZ), forming Y-shaped axoneme-to-membrane connectors via its coiled-coil and C2 domains; it coordinates two TZ modules (MKS and NPHP) at basal body-associated transition fibres and TZ to seal the ciliary compartment; it establishes a ciliary zone of exclusion (CIZE) that confines GPCRs and NPHP-2/inversin to distal cilia and limits PIP2 ciliary abundance.","method":"C. elegans genetics; electron microscopy (TZ ultrastructure); domain deletion analysis; genetic interaction studies; lipid/signaling assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — structural ultrastructure (EM), domain mutagenesis, genetic epistasis in multiple modules, multiple orthogonal methods, single rigorous study","pmids":["26392567"],"is_preprint":false},{"year":2015,"finding":"Rpgrip1l regulates proteasomal activity specifically at the basal body/ciliary base; Psmd2 (a component of the regulatory 19S proteasomal subunit) is an interaction partner of Rpgrip1l; in Rpgrip1l-/- mouse embryos, proteasomal components localize to cilia but proteasomal activity is decreased in a cilia-dependent manner, disturbing Shh signaling.","method":"Rpgrip1l-/- mouse embryo analysis; co-immunoprecipitation (Rpgrip1l–Psmd2); quantification of proteasomal substrates; proteasomal activity assay; Shh signaling analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with defined molecular phenotype, Co-IP of proteasome subunit, activity assays, multiple readouts, single rigorous study","pmids":["26150391"],"is_preprint":false},{"year":2016,"finding":"CEP-290 in C. elegans depends on the coiled-coil region of MKS-5 (Rpgrip1L ortholog) for TZ localization, and MKS-5/Rpgrip1L acts upstream in an MKS-5- and CEP-290-dependent assembly pathway for the TZ.","method":"C. elegans genetics; interdependent localization hierarchy analysis; immunofluorescence","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis and localization hierarchy in C. elegans, single lab, two orthogonal methods","pmids":["26982032"],"is_preprint":false},{"year":2016,"finding":"In vivo manipulation (knockdown/knockout) of Rpgrip1l in mice reduces adiposity and hyperphagia through diminished leptin sensitivity specifically in Leprb-expressing neurons.","method":"In vivo mouse genetics; leptin sensitivity assays; neuron-specific manipulation","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse genetic model with specific neuronal targeting and defined signaling phenotype, single lab","pmids":["27064284"],"is_preprint":false},{"year":2017,"finding":"Myosin Va (MyoVa) interacts with RPGRIP1L via residues near or in the Rab11a-binding site within MyoVa's globular tail domain (GTD) and the C2 domains of RPGRIP1L; MyoVa and RPGRIP1L interact near the cilium base in ciliated RPE cells; dominant-negative MyoVa constructs result in mostly unciliated RPE cells.","method":"Yeast two-hybrid; co-immunoprecipitation; proximity ligation assay; dominant-negative expression in RPE cells","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus PLA plus functional dominant-negative assay, single lab","pmids":["28266547"],"is_preprint":false},{"year":2018,"finding":"RPGRIP1L deficiency in mouse embryos causes decreased autophagic activity due to increased activation of MTORC1; rapamycin rescues dysregulated MTORC1, autophagic activity, and cilia length but not proteasomal activity, demonstrating that RPGRIP1L regulates autophagic and proteasomal activity independently.","method":"Rpgrip1l-/- mouse embryo analysis; MTORC1 activity assays; rapamycin rescue experiments; autophagic flux assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with pharmacological rescue, multiple orthogonal readouts, single lab","pmids":["29372668"],"is_preprint":false},{"year":2018,"finding":"RPGRIP1L regulates desmoglein endocytosis in keratinocytes independently of cilia: RPGRIP1L knockdown induces spontaneous desmoglein endocytosis (AK23 labeling and biotinylation assays), and inhibiting endocytosis with dynasore or sucrose rescues desmosomal phenotypes. This function is cilia-independent as demonstrated in HaCaT cells lacking primary cilia.","method":"Gene knockdown (Rpgrip1l KO mice and HaCaT cells); AK23 labeling; surface biotinylation assays; dynasore/sucrose rescue; immunofluorescence","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse plus cell line KD, multiple orthogonal methods, pharmacological rescue, cilia-independent mechanism established","pmids":["30689641"],"is_preprint":false},{"year":2018,"finding":"RPGRex1-19 (but not RPGRskip14/15) forms interaction complexes with RPGRIP1L, as demonstrated by co-immunoprecipitation in HEK293T cells expressing specific RPGR isoforms; this indicates isoform-specific binding mediated by alternative splicing of RPGR.","method":"Co-immunoprecipitation in CRISPR-engineered HEK293T cells expressing specific RPGR isoforms","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP in isogenic CRISPR cell lines, single lab, isoform-specific result","pmids":["33808286"],"is_preprint":false},{"year":2019,"finding":"Congenital and adult-onset deletion of Rpgrip1l in Pomc-expressing neurons causes hyperphagia and obesity associated with reduction in the Pomc/Npy neuronal number ratio and increased ARH-PVH axonal projections; biallelic RPGRIP1L mutations in iPSC-derived neurons produce fewer cilia-positive neurons and blunted SHH responses.","method":"Conditional KO mouse (Pomc-Cre); neuronal counting; axonal projection analysis; iPSC-derived neuron modeling; SHH response assay","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with specific neuronal phenotype plus human iPSC validation, single lab, two orthogonal models","pmids":["30728336"],"is_preprint":false},{"year":2019,"finding":"In Ftm/Rpgrip1l-/- mouse embryos, Shh expression is lost in the ventral forebrain (but maintained in the ZLI) and Gli activity is severely downregulated; reintroduction of the repressor form of Gli3 into the Ftm-/- background rescues optic cup formation, demonstrating region-specific modulation of Hh/Gli activator-to-repressor ratio by Rpgrip1l.","method":"Rpgrip1l-/- mouse embryo analysis; in situ hybridization for Shh; Gli activity assays; genetic rescue (Gli3 repressor reintroduction)","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with genetic epistasis (Gli3 rescue), specific Shh/Gli pathway readouts, single lab","pmids":["30692221"],"is_preprint":false},{"year":2021,"finding":"Rpgrip1l governs ciliary gating by ensuring the proper amount of Cep290 at the vertebrate transition zone; loss of Rpgrip1l reduces Cep290 at the TZ, impairing ciliary protein entry/exit gating; the flavonoid eupatilin rescues ciliary gating in Rpgrip1l-deficient cells.","method":"Rpgrip1l-/- mouse embryo analysis; Cep290 quantification at TZ; ciliary gating assays; pharmacological rescue with eupatilin","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO model plus pharmacological rescue, quantitative TZ analysis, single lab","pmids":["33625872"],"is_preprint":false},{"year":2018,"finding":"In Chlamydomonas reinhardtii, RPGRIP1L (RPG1) is required for proper localization of NPHP4 at the transition zone and acts as part of the ciliary gate for cytoplasmic proteins (but not IFT proteins); rpg1 mutant cilia show dramatic increase in cytoplasmic proteins (involved in translation, membrane remodeling, ATP production, chaperonins), indicating RPGRIP1L excludes non-ciliary proteins from the cilium.","method":"Chlamydomonas mutant analysis; mass spectrometry-based ciliary proteome comparison; NPHP4 localization by immunofluorescence","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — mass spectrometry proteomics plus localization in algal model organism, single lab","pmids":["30237221"],"is_preprint":false},{"year":2023,"finding":"The N-terminal coiled-coil regions (CC12) of Rpgrip1l each form stable parallel dimers; overexpression of CC12 in NIH/3T3 cells significantly shortens primary cilia length dependent on dimer formation; disease-related mutations can alter the dimeric states of CC12.","method":"Crystallography/structural characterization; biochemical dimerization assays; overexpression in NIH/3T3 cells with cilia length measurement; disease mutation analysis","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — structural characterization plus functional cellular assay plus disease mutation analysis, single lab","pmids":["36915689"],"is_preprint":false},{"year":2011,"finding":"C. elegans NPHP-8 (homologue of RPGRIP1L) co-localizes with NPHP-4 at the transition zone at the base of cilia; nphp-8 mutation leads to shorter cilia in a subset of ciliary neurons and impaired chemosensation, establishing a role in ciliogenesis and cilia-mediated sensory function.","method":"C. elegans genetics; immunofluorescence colocalization; dye-filling assay; chemotaxis assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with cellular and behavioral phenotype, colocalization with NPHP4, single lab","pmids":["21689635"],"is_preprint":false},{"year":2025,"finding":"In RPGRIP1L-deficient human cerebellar organoids, FGF/MAPK signaling pathway is overactivated (with MEK1/2 pathway effectors enriched at cilia base), causing impaired neurogenesis, increased progenitor proliferation, and severe reduction in Purkinje cell markers; pharmacological inhibition of FGF receptors reduces MEK1/2 activation at cilia base and rescues both proliferative-neurogenic balance and Purkinje lineage formation.","method":"Human iPSC-derived cerebellar organoids with RPGRIP1L null mutations or patient variants; immunofluorescence; pharmacological FGF receptor inhibition rescue","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human iPSC organoid model with pharmacological rescue and mechanistic pathway identification, single lab, preprint","pmids":["bio_10.1101_2025.04.14.648790"],"is_preprint":true}],"current_model":"RPGRIP1L is a scaffold protein that localizes to the transition zone (TZ) of primary cilia and the basal body, where it acts as an assembly factor for TZ ultrastructure by coordinating MKS and NPHP protein modules; it establishes the ciliary diffusion barrier/gate to control ciliary protein composition and PIP2 abundance, regulates proteasomal activity (via interaction with Psmd2) and autophagy (via MTORC1) at the ciliary base, modulates Hedgehog/Gli and FGF/MAPK signaling, stabilizes Dishevelled to control planar cell polarity, controls leptin receptor trafficking to the cilium to mediate leptin sensitivity, regulates desmoglein endocytosis in a cilia-independent manner, and interacts with multiple partners including nephrocystin-4 (NPHP4), RPGR, NEK4, Myosin Va, and Cep290 to coordinate ciliary signaling across diverse cell types."},"narrative":{"mechanistic_narrative":"RPGRIP1L is a ciliary transition zone (TZ) scaffold protein that assembles and seals the gate at the base of the primary cilium to control ciliary protein composition and signaling [PMID:26392567]. It functions as a TZ assembly factor, forming Y-shaped axoneme-to-membrane connectors through its coiled-coil and C2 domains and coordinating the MKS and NPHP protein modules to establish a ciliary zone of exclusion that confines GPCRs and inversin to the distal cilium and limits ciliary PIP2 [PMID:26392567]; its N-terminal coiled-coil regions form parallel dimers required for proper cilia length, and disease mutations perturb this dimerization [PMID:36915689]. RPGRIP1L acts upstream in TZ assembly by recruiting the proper amount of CEP290 to gate ciliary protein entry and exit [PMID:26982032, PMID:33625872], and excludes non-ciliary cytoplasmic proteins from the cilium while positioning NPHP4 at the TZ [PMID:30237221]. It interacts with nephrocystin-4, RPGR, NEK4, and Myosin Va near the ciliary base, partnerships that support ciliogenesis and are disrupted by ciliopathy-associated mutations [PMID:17558409, PMID:19430481, PMID:21685204, PMID:28266547]. At the ciliary base RPGRIP1L tunes proteostasis—maintaining proteasomal activity through interaction with the 19S subunit Psmd2 and restraining MTORC1 to permit autophagy, two functions it executes independently [PMID:26150391, PMID:29372668]. Through gating and proteostasis it modulates Hedgehog/Gli signaling by setting the Gli activator-to-repressor ratio [PMID:26150391, PMID:30692221] and restrains FGF/MAPK signaling at the cilia base during neurogenesis [PMID:bio_10.1101_2025.04.14.648790], and it stabilizes Dishevelled within an inversin–NPHP4 complex to direct basal-body positioning and planar cell polarity [PMID:22927466]. In the hypothalamus it promotes trafficking of the leptin receptor toward the cilium to enable leptin-induced STAT3 signaling, such that its loss produces hyperphagia and obesity [PMID:21037323, PMID:24807221, PMID:27064284]. Distinct from its ciliary roles, RPGRIP1L restrains desmoglein endocytosis in keratinocytes in a cilia-independent manner [PMID:30689641].","teleology":[{"year":2007,"claim":"Established RPGRIP1L as a basal body/centrosome-associated protein that physically binds nephrocystin-4, linking it to the nephronophthisis-ciliopathy protein network and explaining its mutation in ciliopathies.","evidence":"Colocalization imaging and reciprocal co-immunoprecipitation with disease-mutation disruption","pmids":["17558409","17558407"],"confidence":"Medium","gaps":["Did not define the structural basis of the NPHP4 interaction","Did not establish the molecular function performed at the basal body"]},{"year":2009,"claim":"Identified RPGRIP1L as a binding partner of RPGR whose common variant modifies retinal degeneration, and uncovered a parallel cilia-independent interaction with thromboxane A2 receptors that dampens receptor signaling.","evidence":"Co-immunoprecipitation with allele-specific disruption and genetic modifier analysis; yeast two-hybrid plus functional signaling assays","pmids":["19430481","19464661"],"confidence":"Medium","gaps":["RPGR interaction surface not mapped","Physiological relevance of the thromboxane receptor interaction in vivo unestablished"]},{"year":2010,"claim":"Connected RPGRIP1L to energy homeostasis by showing it is required for leptin receptor trafficking to the cilium and downstream STAT3 activation, and is transcriptionally controlled by CUX1 at the FTO locus.","evidence":"siRNA knockdown, promoter-probe assays, leptin receptor immunofluorescence and pStat3 western blot in hypothalamic/neuroblastoma cells","pmids":["21037323"],"confidence":"Medium","gaps":["Mechanism of receptor recruitment to the cilium not defined","In vitro cell-line evidence only at this stage"]},{"year":2011,"claim":"Defined ciliogenic partners and conserved function: RPGRIP1L forms a complex with the kinase NEK4 needed for cilium assembly, while its C. elegans ortholog colocalizes with NPHP-4 at the TZ and supports sensory cilia and chemosensation.","evidence":"Tandem affinity purification/mass spectrometry and knockdown in mammalian cells; C. elegans genetics with dye-filling and chemotaxis assays","pmids":["21685204","21689635"],"confidence":"Medium","gaps":["Whether NEK4 phosphorylates RPGRIP1L unknown","Substrate of NEK4 at the basal body not identified"]},{"year":2012,"claim":"Showed RPGRIP1L controls planar cell polarity by positioning the basal body and stabilizing Dishevelled within an inversin–NPHP4 complex, demonstrated through rescue in two model organisms.","evidence":"Mouse and zebrafish loss-of-function, rescue experiments, and Co-IP complex analysis","pmids":["22927466"],"confidence":"High","gaps":["Molecular mechanism by which the complex blocks Dishevelled degradation not resolved"]},{"year":2015,"claim":"Provided the core mechanistic model: RPGRIP1L is a TZ assembly factor building Y-link connectors and coordinating MKS and NPHP modules to create a diffusion barrier that excludes GPCRs, inversin, and PIP2 from defined ciliary zones.","evidence":"C. elegans genetics, transition zone electron microscopy, domain-deletion mutagenesis, genetic epistasis, and lipid/signaling assays","pmids":["26392567"],"confidence":"High","gaps":["Stoichiometry of MKS/NPHP module assembly not defined","Direct lipid-binding partner controlling PIP2 not identified"]},{"year":2015,"claim":"Linked RPGRIP1L to ciliary-base proteostasis by identifying the proteasome 19S subunit Psmd2 as a partner and showing RPGRIP1L is required for proteasomal activity that controls Shh signaling.","evidence":"Rpgrip1l-/- mouse embryos, Co-IP of Psmd2, proteasomal substrate and activity assays, Shh readouts","pmids":["26150391"],"confidence":"High","gaps":["How RPGRIP1L stimulates proteasome activity mechanistically unknown","Direct proteasome substrates regulating Shh not enumerated"]},{"year":2016,"claim":"Placed RPGRIP1L upstream of CEP290 in a hierarchical TZ assembly pathway, with its coiled-coil region required for CEP290 recruitment.","evidence":"C. elegans genetics and interdependent localization-hierarchy analysis","pmids":["26982032"],"confidence":"Medium","gaps":["Whether RPGRIP1L–CEP290 interaction is direct not shown","Vertebrate confirmation of the hierarchy not in this study"]},{"year":2017,"claim":"Identified Myosin Va as a partner binding the C2 domains of RPGRIP1L near the cilium base, implicating motor-driven transport in ciliogenesis.","evidence":"Yeast two-hybrid, Co-IP, proximity ligation assay, and dominant-negative expression in RPE cells","pmids":["28266547"],"confidence":"Medium","gaps":["Cargo transported by MyoVa–RPGRIP1L not defined","Functional consequence of disrupting the interaction in vivo untested"]},{"year":2018,"claim":"Separated RPGRIP1L's ciliary and non-ciliary roles: it restrains MTORC1 to permit autophagy independently of its proteasomal function, and independently of cilia it restrains desmoglein endocytosis in keratinocytes.","evidence":"Rpgrip1l-/- mouse embryos with rapamycin rescue and autophagy flux assays; keratinocyte/HaCaT knockdown with biotinylation and dynasore rescue","pmids":["29372668","30689641"],"confidence":"High","gaps":["How RPGRIP1L suppresses MTORC1 mechanistically unknown","Molecular link between RPGRIP1L and the desmoglein endocytic machinery not defined"]},{"year":2018,"claim":"Refined partner specificity, showing isoform-dependent binding to RPGRex1-19, and confirmed in algae that RPGRIP1L positions NPHP4 and excludes cytoplasmic (non-IFT) proteins from the cilium.","evidence":"Co-IP in CRISPR-engineered HEK293T cells; Chlamydomonas mutant ciliary proteomics and NPHP4 localization","pmids":["33808286","30237221"],"confidence":"Medium","gaps":["Functional consequence of RPGR isoform selectivity unresolved","Mechanism distinguishing excluded cytoplasmic proteins from retained IFT proteins unknown"]},{"year":2019,"claim":"Extended the obesity and Hedgehog roles in vivo: RPGRIP1L acts in Pomc and Leprb neurons to control feeding, while in embryos it sets the Gli activator-to-repressor ratio governing forebrain/optic patterning.","evidence":"Conditional Pomc-Cre KO mice, iPSC-derived neurons with SHH assays; Rpgrip1l-/- embryos with Gli3-repressor genetic rescue","pmids":["30728336","30692221"],"confidence":"Medium","gaps":["How ciliary gating translates into region-specific Gli regulation not mechanistically closed","Cell-autonomous versus circuit-level contributions to obesity not fully separated"]},{"year":2021,"claim":"Demonstrated that RPGRIP1L governs ciliary gating by maintaining CEP290 levels at the vertebrate TZ, with the flavonoid eupatilin restoring gating in deficient cells.","evidence":"Rpgrip1l-/- mouse embryos, quantitative TZ CEP290 measurement, ciliary gating assays, eupatilin rescue","pmids":["33625872"],"confidence":"Medium","gaps":["Mechanism of eupatilin rescue unknown","Whether reduced CEP290 fully accounts for gating loss not established"]},{"year":2023,"claim":"Resolved a structural basis for function: the N-terminal coiled-coil region dimerizes as parallel dimers required to maintain cilia length, and disease mutations alter this dimerization.","evidence":"Structural characterization, biochemical dimerization assays, and cilia-length measurement in NIH/3T3 cells","pmids":["36915689"],"confidence":"Medium","gaps":["How dimerization integrates into the full TZ scaffold not shown","Structure of full-length protein and its module-coordinating domains unresolved"]},{"year":2025,"claim":"Implicated RPGRIP1L in restraining FGF/MAPK signaling at the cilia base during human cerebellar neurogenesis, with FGF receptor inhibition rescuing Purkinje lineage formation.","evidence":"Human iPSC cerebellar organoids with RPGRIP1L null/patient variants and pharmacological FGFR inhibition (preprint)","pmids":["bio_10.1101_2025.04.14.648790"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","How loss of ciliary gating leads to FGF/MAPK overactivation mechanistically unknown"]},{"year":null,"claim":"How a single TZ scaffold integrates its diverse outputs—diffusion barrier, proteostasis, and parallel modulation of Hedgehog, FGF/MAPK, Wnt/PCP, and leptin signaling—into context-specific cellular decisions remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking gating defects to specific signaling outcomes","Full-length structure and module-binding interfaces undefined","Mechanism connecting ciliary scaffolding to cilia-independent functions unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[8,6,9]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[12]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[8,18,19,21]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,1,5]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[8,20]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[13]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[17,22,6]}],"complexes":["ciliary transition zone (MKS/NPHP modules)"],"partners":["NPHP4","RPGR","NEK4","MYO5A","PSMD2","CEP290","INVS"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q68CZ1","full_name":"Protein fantom","aliases":["Nephrocystin-8","RPGR-interacting protein 1-like protein","RPGRIP1-like protein"],"length_aa":1315,"mass_kda":151.2,"function":"Negatively regulates signaling through the G-protein coupled thromboxane A2 receptor (TBXA2R) (PubMed:19464661). May be involved in mechanisms like programmed cell death, craniofacial development, patterning of the limbs, and formation of the left-right axis (By similarity). Involved in the organization of apical junctions; the function is proposed to implicate a NPHP1-4-8 module. Does not seem to be strictly required for ciliogenesis (PubMed:19464661). Involved in establishment of planar cell polarity such as in cochlear sensory epithelium and is proposed to implicate stabilization of disheveled proteins (By similarity). Involved in regulation of proteasomal activity at the primary cilium probably implicating association with PSDM2 (By similarity)","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton, cilium basal body; Cytoplasm, cytoskeleton, cilium axoneme; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cell junction, tight junction","url":"https://www.uniprot.org/uniprotkb/Q68CZ1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RPGRIP1L","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RPGRIP1L","total_profiled":1310},"omim":[{"mim_id":"619285","title":"TRANSMEMBRANE PROTEIN 218; TMEM218","url":"https://www.omim.org/entry/619285"},{"mim_id":"619113","title":"COACH SYNDROME 3; COACH3","url":"https://www.omim.org/entry/619113"},{"mim_id":"619111","title":"COACH SYNDROME 2; COACH2","url":"https://www.omim.org/entry/619111"},{"mim_id":"617310","title":"ANKYRIN REPEAT AND STERILE ALPHA MOTIF DOMAINS-CONTAINING PROTEIN 3; ANKS3","url":"https://www.omim.org/entry/617310"},{"mim_id":"615636","title":"JOUBERT SYNDROME 21; JBTS21","url":"https://www.omim.org/entry/615636"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in 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\"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with mutation disruption of interaction, single lab, two orthogonal methods\",\n      \"pmids\": [\"17558409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RPGRIP1L interacts with nephrocystin-4 (NPHP4), and NPHP4 mutations known to cause Senior-Løken syndrome disrupt this interaction; RPGRIP1L protein localizes to basal bodies.\",\n      \"method\": \"Protein-protein interaction analyses; co-immunoprecipitation; subcellular localization imaging\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with disease-mutation disruption, single lab, two orthogonal methods\",\n      \"pmids\": [\"17558407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RPGRIP1L interacts biochemically with RPGR (retinitis pigmentosa GTPase regulator), and the common variant A229T (Thr229-encoded protein) significantly compromises this interaction, thereby modifying retinal degeneration in ciliopathies.\",\n      \"method\": \"Biochemical interaction assay (co-immunoprecipitation); genetic modifier analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with allele-specific disruption, multiple genetic lines of evidence, single lab\",\n      \"pmids\": [\"19430481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RPGRIP1L (KIAA1005/TPIP) directly interacts with the C-terminal region of both thromboxane A2 receptor isoforms TPα and TPβ, reduces cell-surface TP levels, and negatively regulates TP-mediated phosphoinositide hydrolysis, ERK1/2 phosphorylation, and IL-6 production.\",\n      \"method\": \"Yeast two-hybrid; co-immunoprecipitation in HEK293 cells; functional signaling assays\",\n      \"journal\": \"Prostaglandins & other lipid mediators\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus functional readouts, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"19464661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Reduced expression of Rpgrip1l impairs leptin receptor isoform b (Leprb) trafficking to the vicinity of the cilium in hypothalamic/neuroblastoma cells in vitro, and this trafficking to the cilium coincides with increased leptin signaling (pStat3). CUX1 isoforms P200 and P110 regulate RPGRIP1L expression via a conserved AATAAATA element in the FTO intronic region.\",\n      \"method\": \"siRNA knockdown; promoter-probe assays; immunofluorescence for leptin receptor clustering; pStat3 western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (knockdown, promoter assay, receptor trafficking, signaling readout), single lab\",\n      \"pmids\": [\"21037323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RPGRIP1L and RPGRIP1 each form a complex with the serine/threonine kinase NEK4, identified by tandem affinity purification and mass spectrometry; NEK4 localizes to basal bodies in ciliated cells and to the ciliary rootlet in ciliated organs. Downregulation of NEK4 significantly decreases cilium assembly.\",\n      \"method\": \"Tandem affinity purification combined with mass spectrometry; immunofluorescence; siRNA knockdown\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TAP-MS identification of complex plus localization plus functional knockdown, single lab\",\n      \"pmids\": [\"21685204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Rpgrip1l is required for planar cell polarity: it positions the basal body along the planar polarity axis in mouse cochlea and zebrafish floor plate, stabilizes Dishevelled at the cilium base, and forms a complex with inversin and nephrocystin-4 that prevents Dishevelled degradation. Rescue experiments in zebrafish showed that the planar polarity function of Rpgrip1l is mediated through Dishevelled stabilization.\",\n      \"method\": \"Mouse and zebrafish genetic loss-of-function; rescue experiments; co-immunoprecipitation complex analysis; immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function in two model organisms, rescue experiments, Co-IP complex, multiple orthogonal methods, specific cellular phenotype\",\n      \"pmids\": [\"22927466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Rpgrip1l hypomorphic (Rpgrip1l+/-) mice are hyperphagic and obese, display diminished suppression of food intake in response to leptin, reduced AcIII-positive cilia in the hypothalamus, and impaired convening of the leptin receptor to the vicinity of the cilium accompanied by diminished pStat3 in response to leptin.\",\n      \"method\": \"Mouse hypomorphic genetics; leptin challenge assays; immunofluorescence for cilia and leptin receptor; pStat3 measurement\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse genetic model plus human fibroblast validation, multiple orthogonal methods, replicated across labs\",\n      \"pmids\": [\"24807221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Rpgrip1l (MKS-5 in C. elegans) functions as an assembly factor for the ciliary transition zone (TZ), forming Y-shaped axoneme-to-membrane connectors via its coiled-coil and C2 domains; it coordinates two TZ modules (MKS and NPHP) at basal body-associated transition fibres and TZ to seal the ciliary compartment; it establishes a ciliary zone of exclusion (CIZE) that confines GPCRs and NPHP-2/inversin to distal cilia and limits PIP2 ciliary abundance.\",\n      \"method\": \"C. elegans genetics; electron microscopy (TZ ultrastructure); domain deletion analysis; genetic interaction studies; lipid/signaling assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — structural ultrastructure (EM), domain mutagenesis, genetic epistasis in multiple modules, multiple orthogonal methods, single rigorous study\",\n      \"pmids\": [\"26392567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Rpgrip1l regulates proteasomal activity specifically at the basal body/ciliary base; Psmd2 (a component of the regulatory 19S proteasomal subunit) is an interaction partner of Rpgrip1l; in Rpgrip1l-/- mouse embryos, proteasomal components localize to cilia but proteasomal activity is decreased in a cilia-dependent manner, disturbing Shh signaling.\",\n      \"method\": \"Rpgrip1l-/- mouse embryo analysis; co-immunoprecipitation (Rpgrip1l–Psmd2); quantification of proteasomal substrates; proteasomal activity assay; Shh signaling analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with defined molecular phenotype, Co-IP of proteasome subunit, activity assays, multiple readouts, single rigorous study\",\n      \"pmids\": [\"26150391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CEP-290 in C. elegans depends on the coiled-coil region of MKS-5 (Rpgrip1L ortholog) for TZ localization, and MKS-5/Rpgrip1L acts upstream in an MKS-5- and CEP-290-dependent assembly pathway for the TZ.\",\n      \"method\": \"C. elegans genetics; interdependent localization hierarchy analysis; immunofluorescence\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis and localization hierarchy in C. elegans, single lab, two orthogonal methods\",\n      \"pmids\": [\"26982032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In vivo manipulation (knockdown/knockout) of Rpgrip1l in mice reduces adiposity and hyperphagia through diminished leptin sensitivity specifically in Leprb-expressing neurons.\",\n      \"method\": \"In vivo mouse genetics; leptin sensitivity assays; neuron-specific manipulation\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse genetic model with specific neuronal targeting and defined signaling phenotype, single lab\",\n      \"pmids\": [\"27064284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Myosin Va (MyoVa) interacts with RPGRIP1L via residues near or in the Rab11a-binding site within MyoVa's globular tail domain (GTD) and the C2 domains of RPGRIP1L; MyoVa and RPGRIP1L interact near the cilium base in ciliated RPE cells; dominant-negative MyoVa constructs result in mostly unciliated RPE cells.\",\n      \"method\": \"Yeast two-hybrid; co-immunoprecipitation; proximity ligation assay; dominant-negative expression in RPE cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus PLA plus functional dominant-negative assay, single lab\",\n      \"pmids\": [\"28266547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RPGRIP1L deficiency in mouse embryos causes decreased autophagic activity due to increased activation of MTORC1; rapamycin rescues dysregulated MTORC1, autophagic activity, and cilia length but not proteasomal activity, demonstrating that RPGRIP1L regulates autophagic and proteasomal activity independently.\",\n      \"method\": \"Rpgrip1l-/- mouse embryo analysis; MTORC1 activity assays; rapamycin rescue experiments; autophagic flux assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with pharmacological rescue, multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"29372668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RPGRIP1L regulates desmoglein endocytosis in keratinocytes independently of cilia: RPGRIP1L knockdown induces spontaneous desmoglein endocytosis (AK23 labeling and biotinylation assays), and inhibiting endocytosis with dynasore or sucrose rescues desmosomal phenotypes. This function is cilia-independent as demonstrated in HaCaT cells lacking primary cilia.\",\n      \"method\": \"Gene knockdown (Rpgrip1l KO mice and HaCaT cells); AK23 labeling; surface biotinylation assays; dynasore/sucrose rescue; immunofluorescence\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse plus cell line KD, multiple orthogonal methods, pharmacological rescue, cilia-independent mechanism established\",\n      \"pmids\": [\"30689641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RPGRex1-19 (but not RPGRskip14/15) forms interaction complexes with RPGRIP1L, as demonstrated by co-immunoprecipitation in HEK293T cells expressing specific RPGR isoforms; this indicates isoform-specific binding mediated by alternative splicing of RPGR.\",\n      \"method\": \"Co-immunoprecipitation in CRISPR-engineered HEK293T cells expressing specific RPGR isoforms\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP in isogenic CRISPR cell lines, single lab, isoform-specific result\",\n      \"pmids\": [\"33808286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Congenital and adult-onset deletion of Rpgrip1l in Pomc-expressing neurons causes hyperphagia and obesity associated with reduction in the Pomc/Npy neuronal number ratio and increased ARH-PVH axonal projections; biallelic RPGRIP1L mutations in iPSC-derived neurons produce fewer cilia-positive neurons and blunted SHH responses.\",\n      \"method\": \"Conditional KO mouse (Pomc-Cre); neuronal counting; axonal projection analysis; iPSC-derived neuron modeling; SHH response assay\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with specific neuronal phenotype plus human iPSC validation, single lab, two orthogonal models\",\n      \"pmids\": [\"30728336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In Ftm/Rpgrip1l-/- mouse embryos, Shh expression is lost in the ventral forebrain (but maintained in the ZLI) and Gli activity is severely downregulated; reintroduction of the repressor form of Gli3 into the Ftm-/- background rescues optic cup formation, demonstrating region-specific modulation of Hh/Gli activator-to-repressor ratio by Rpgrip1l.\",\n      \"method\": \"Rpgrip1l-/- mouse embryo analysis; in situ hybridization for Shh; Gli activity assays; genetic rescue (Gli3 repressor reintroduction)\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with genetic epistasis (Gli3 rescue), specific Shh/Gli pathway readouts, single lab\",\n      \"pmids\": [\"30692221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Rpgrip1l governs ciliary gating by ensuring the proper amount of Cep290 at the vertebrate transition zone; loss of Rpgrip1l reduces Cep290 at the TZ, impairing ciliary protein entry/exit gating; the flavonoid eupatilin rescues ciliary gating in Rpgrip1l-deficient cells.\",\n      \"method\": \"Rpgrip1l-/- mouse embryo analysis; Cep290 quantification at TZ; ciliary gating assays; pharmacological rescue with eupatilin\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO model plus pharmacological rescue, quantitative TZ analysis, single lab\",\n      \"pmids\": [\"33625872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In Chlamydomonas reinhardtii, RPGRIP1L (RPG1) is required for proper localization of NPHP4 at the transition zone and acts as part of the ciliary gate for cytoplasmic proteins (but not IFT proteins); rpg1 mutant cilia show dramatic increase in cytoplasmic proteins (involved in translation, membrane remodeling, ATP production, chaperonins), indicating RPGRIP1L excludes non-ciliary proteins from the cilium.\",\n      \"method\": \"Chlamydomonas mutant analysis; mass spectrometry-based ciliary proteome comparison; NPHP4 localization by immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mass spectrometry proteomics plus localization in algal model organism, single lab\",\n      \"pmids\": [\"30237221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The N-terminal coiled-coil regions (CC12) of Rpgrip1l each form stable parallel dimers; overexpression of CC12 in NIH/3T3 cells significantly shortens primary cilia length dependent on dimer formation; disease-related mutations can alter the dimeric states of CC12.\",\n      \"method\": \"Crystallography/structural characterization; biochemical dimerization assays; overexpression in NIH/3T3 cells with cilia length measurement; disease mutation analysis\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural characterization plus functional cellular assay plus disease mutation analysis, single lab\",\n      \"pmids\": [\"36915689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"C. elegans NPHP-8 (homologue of RPGRIP1L) co-localizes with NPHP-4 at the transition zone at the base of cilia; nphp-8 mutation leads to shorter cilia in a subset of ciliary neurons and impaired chemosensation, establishing a role in ciliogenesis and cilia-mediated sensory function.\",\n      \"method\": \"C. elegans genetics; immunofluorescence colocalization; dye-filling assay; chemotaxis assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with cellular and behavioral phenotype, colocalization with NPHP4, single lab\",\n      \"pmids\": [\"21689635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In RPGRIP1L-deficient human cerebellar organoids, FGF/MAPK signaling pathway is overactivated (with MEK1/2 pathway effectors enriched at cilia base), causing impaired neurogenesis, increased progenitor proliferation, and severe reduction in Purkinje cell markers; pharmacological inhibition of FGF receptors reduces MEK1/2 activation at cilia base and rescues both proliferative-neurogenic balance and Purkinje lineage formation.\",\n      \"method\": \"Human iPSC-derived cerebellar organoids with RPGRIP1L null mutations or patient variants; immunofluorescence; pharmacological FGF receptor inhibition rescue\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human iPSC organoid model with pharmacological rescue and mechanistic pathway identification, single lab, preprint\",\n      \"pmids\": [\"bio_10.1101_2025.04.14.648790\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"RPGRIP1L is a scaffold protein that localizes to the transition zone (TZ) of primary cilia and the basal body, where it acts as an assembly factor for TZ ultrastructure by coordinating MKS and NPHP protein modules; it establishes the ciliary diffusion barrier/gate to control ciliary protein composition and PIP2 abundance, regulates proteasomal activity (via interaction with Psmd2) and autophagy (via MTORC1) at the ciliary base, modulates Hedgehog/Gli and FGF/MAPK signaling, stabilizes Dishevelled to control planar cell polarity, controls leptin receptor trafficking to the cilium to mediate leptin sensitivity, regulates desmoglein endocytosis in a cilia-independent manner, and interacts with multiple partners including nephrocystin-4 (NPHP4), RPGR, NEK4, Myosin Va, and Cep290 to coordinate ciliary signaling across diverse cell types.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RPGRIP1L is a ciliary transition zone (TZ) scaffold protein that assembles and seals the gate at the base of the primary cilium to control ciliary protein composition and signaling [#8]. It functions as a TZ assembly factor, forming Y-shaped axoneme-to-membrane connectors through its coiled-coil and C2 domains and coordinating the MKS and NPHP protein modules to establish a ciliary zone of exclusion that confines GPCRs and inversin to the distal cilium and limits ciliary PIP2 [#8]; its N-terminal coiled-coil regions form parallel dimers required for proper cilia length, and disease mutations perturb this dimerization [#20]. RPGRIP1L acts upstream in TZ assembly by recruiting the proper amount of CEP290 to gate ciliary protein entry and exit [#10, #18], and excludes non-ciliary cytoplasmic proteins from the cilium while positioning NPHP4 at the TZ [#19]. It interacts with nephrocystin-4, RPGR, NEK4, and Myosin Va near the ciliary base, partnerships that support ciliogenesis and are disrupted by ciliopathy-associated mutations [#0, #2, #5, #12]. At the ciliary base RPGRIP1L tunes proteostasis—maintaining proteasomal activity through interaction with the 19S subunit Psmd2 and restraining MTORC1 to permit autophagy, two functions it executes independently [#9, #13]. Through gating and proteostasis it modulates Hedgehog/Gli signaling by setting the Gli activator-to-repressor ratio [#9, #17] and restrains FGF/MAPK signaling at the cilia base during neurogenesis [#22], and it stabilizes Dishevelled within an inversin–NPHP4 complex to direct basal-body positioning and planar cell polarity [#6]. In the hypothalamus it promotes trafficking of the leptin receptor toward the cilium to enable leptin-induced STAT3 signaling, such that its loss produces hyperphagia and obesity [#4, #7, #11]. Distinct from its ciliary roles, RPGRIP1L restrains desmoglein endocytosis in keratinocytes in a cilia-independent manner [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established RPGRIP1L as a basal body/centrosome-associated protein that physically binds nephrocystin-4, linking it to the nephronophthisis-ciliopathy protein network and explaining its mutation in ciliopathies.\",\n      \"evidence\": \"Colocalization imaging and reciprocal co-immunoprecipitation with disease-mutation disruption\",\n      \"pmids\": [\"17558409\", \"17558407\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the structural basis of the NPHP4 interaction\", \"Did not establish the molecular function performed at the basal body\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified RPGRIP1L as a binding partner of RPGR whose common variant modifies retinal degeneration, and uncovered a parallel cilia-independent interaction with thromboxane A2 receptors that dampens receptor signaling.\",\n      \"evidence\": \"Co-immunoprecipitation with allele-specific disruption and genetic modifier analysis; yeast two-hybrid plus functional signaling assays\",\n      \"pmids\": [\"19430481\", \"19464661\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RPGR interaction surface not mapped\", \"Physiological relevance of the thromboxane receptor interaction in vivo unestablished\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected RPGRIP1L to energy homeostasis by showing it is required for leptin receptor trafficking to the cilium and downstream STAT3 activation, and is transcriptionally controlled by CUX1 at the FTO locus.\",\n      \"evidence\": \"siRNA knockdown, promoter-probe assays, leptin receptor immunofluorescence and pStat3 western blot in hypothalamic/neuroblastoma cells\",\n      \"pmids\": [\"21037323\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of receptor recruitment to the cilium not defined\", \"In vitro cell-line evidence only at this stage\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined ciliogenic partners and conserved function: RPGRIP1L forms a complex with the kinase NEK4 needed for cilium assembly, while its C. elegans ortholog colocalizes with NPHP-4 at the TZ and supports sensory cilia and chemosensation.\",\n      \"evidence\": \"Tandem affinity purification/mass spectrometry and knockdown in mammalian cells; C. elegans genetics with dye-filling and chemotaxis assays\",\n      \"pmids\": [\"21685204\", \"21689635\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether NEK4 phosphorylates RPGRIP1L unknown\", \"Substrate of NEK4 at the basal body not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed RPGRIP1L controls planar cell polarity by positioning the basal body and stabilizing Dishevelled within an inversin–NPHP4 complex, demonstrated through rescue in two model organisms.\",\n      \"evidence\": \"Mouse and zebrafish loss-of-function, rescue experiments, and Co-IP complex analysis\",\n      \"pmids\": [\"22927466\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which the complex blocks Dishevelled degradation not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided the core mechanistic model: RPGRIP1L is a TZ assembly factor building Y-link connectors and coordinating MKS and NPHP modules to create a diffusion barrier that excludes GPCRs, inversin, and PIP2 from defined ciliary zones.\",\n      \"evidence\": \"C. elegans genetics, transition zone electron microscopy, domain-deletion mutagenesis, genetic epistasis, and lipid/signaling assays\",\n      \"pmids\": [\"26392567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of MKS/NPHP module assembly not defined\", \"Direct lipid-binding partner controlling PIP2 not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked RPGRIP1L to ciliary-base proteostasis by identifying the proteasome 19S subunit Psmd2 as a partner and showing RPGRIP1L is required for proteasomal activity that controls Shh signaling.\",\n      \"evidence\": \"Rpgrip1l-/- mouse embryos, Co-IP of Psmd2, proteasomal substrate and activity assays, Shh readouts\",\n      \"pmids\": [\"26150391\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RPGRIP1L stimulates proteasome activity mechanistically unknown\", \"Direct proteasome substrates regulating Shh not enumerated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed RPGRIP1L upstream of CEP290 in a hierarchical TZ assembly pathway, with its coiled-coil region required for CEP290 recruitment.\",\n      \"evidence\": \"C. elegans genetics and interdependent localization-hierarchy analysis\",\n      \"pmids\": [\"26982032\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether RPGRIP1L–CEP290 interaction is direct not shown\", \"Vertebrate confirmation of the hierarchy not in this study\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified Myosin Va as a partner binding the C2 domains of RPGRIP1L near the cilium base, implicating motor-driven transport in ciliogenesis.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, proximity ligation assay, and dominant-negative expression in RPE cells\",\n      \"pmids\": [\"28266547\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cargo transported by MyoVa–RPGRIP1L not defined\", \"Functional consequence of disrupting the interaction in vivo untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Separated RPGRIP1L's ciliary and non-ciliary roles: it restrains MTORC1 to permit autophagy independently of its proteasomal function, and independently of cilia it restrains desmoglein endocytosis in keratinocytes.\",\n      \"evidence\": \"Rpgrip1l-/- mouse embryos with rapamycin rescue and autophagy flux assays; keratinocyte/HaCaT knockdown with biotinylation and dynasore rescue\",\n      \"pmids\": [\"29372668\", \"30689641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RPGRIP1L suppresses MTORC1 mechanistically unknown\", \"Molecular link between RPGRIP1L and the desmoglein endocytic machinery not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Refined partner specificity, showing isoform-dependent binding to RPGRex1-19, and confirmed in algae that RPGRIP1L positions NPHP4 and excludes cytoplasmic (non-IFT) proteins from the cilium.\",\n      \"evidence\": \"Co-IP in CRISPR-engineered HEK293T cells; Chlamydomonas mutant ciliary proteomics and NPHP4 localization\",\n      \"pmids\": [\"33808286\", \"30237221\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of RPGR isoform selectivity unresolved\", \"Mechanism distinguishing excluded cytoplasmic proteins from retained IFT proteins unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended the obesity and Hedgehog roles in vivo: RPGRIP1L acts in Pomc and Leprb neurons to control feeding, while in embryos it sets the Gli activator-to-repressor ratio governing forebrain/optic patterning.\",\n      \"evidence\": \"Conditional Pomc-Cre KO mice, iPSC-derived neurons with SHH assays; Rpgrip1l-/- embryos with Gli3-repressor genetic rescue\",\n      \"pmids\": [\"30728336\", \"30692221\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How ciliary gating translates into region-specific Gli regulation not mechanistically closed\", \"Cell-autonomous versus circuit-level contributions to obesity not fully separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated that RPGRIP1L governs ciliary gating by maintaining CEP290 levels at the vertebrate TZ, with the flavonoid eupatilin restoring gating in deficient cells.\",\n      \"evidence\": \"Rpgrip1l-/- mouse embryos, quantitative TZ CEP290 measurement, ciliary gating assays, eupatilin rescue\",\n      \"pmids\": [\"33625872\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of eupatilin rescue unknown\", \"Whether reduced CEP290 fully accounts for gating loss not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved a structural basis for function: the N-terminal coiled-coil region dimerizes as parallel dimers required to maintain cilia length, and disease mutations alter this dimerization.\",\n      \"evidence\": \"Structural characterization, biochemical dimerization assays, and cilia-length measurement in NIH/3T3 cells\",\n      \"pmids\": [\"36915689\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How dimerization integrates into the full TZ scaffold not shown\", \"Structure of full-length protein and its module-coordinating domains unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated RPGRIP1L in restraining FGF/MAPK signaling at the cilia base during human cerebellar neurogenesis, with FGF receptor inhibition rescuing Purkinje lineage formation.\",\n      \"evidence\": \"Human iPSC cerebellar organoids with RPGRIP1L null/patient variants and pharmacological FGFR inhibition (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.04.14.648790\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"How loss of ciliary gating leads to FGF/MAPK overactivation mechanistically unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single TZ scaffold integrates its diverse outputs—diffusion barrier, proteostasis, and parallel modulation of Hedgehog, FGF/MAPK, Wnt/PCP, and leptin signaling—into context-specific cellular decisions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking gating defects to specific signaling outcomes\", \"Full-length structure and module-binding interfaces undefined\", \"Mechanism connecting ciliary scaffolding to cilia-independent functions unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [8, 6, 9]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [8, 18, 19, 21]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 1, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0007224\", \"supporting_discovery_ids\": [9, 17]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [8, 20]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [17, 22, 6]}\n    ],\n    \"complexes\": [\"ciliary transition zone (MKS/NPHP modules)\"],\n    \"partners\": [\"NPHP4\", \"RPGR\", \"NEK4\", \"MYO5A\", \"PSMD2\", \"CEP290\", \"INVS\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}